ABSTRACT First available in 2014, direct-acting antivirals (DAAs) are a highly effective and well-tolerated curative therapy for people infected with hepatitis C virus (HCV) and offer the first real opportunity to achieve HCV elimination. The availability of DAAs alone, however, is not translating to widespread treatment initiation among marginalized groups living with HCV, particularly those engaged in illicit drug use. Achieving HCV elimination requires a concerted public health response that must be directed through evidence-based decision-making focused on how best to reduce the burden in the most-impacted subgroups. To address this need, we propose to generate new Continuum of Care (CoC) estimates and evidence- based elimination roadmaps ? two essential tools to achieve elimination ? that include current needs of key high-risk subgroups who bear the greatest burden of disease: young people who inject drugs, men who have sex with men and inject drugs, and transgender women. In collaboration with End Hep C SF ? a new collective action consortium of public health, academic, and community advocates in San Francisco ? our research team established the first citywide HCV seroprevalence estimate in 2016 for San Francisco's general population, overall and by broadly define risk groups (e.g., young people who inject drugs and men who have sex with men). In this R21, we propose to again partner with End Hep C SF to apply a multi-method epidemiological approach to estimate the population of these 3 high-risk subgroups at four stages of the CoC: (1) screened chronic infection, (2) RNA-confirmed infection, (3) DAA treatment engaged, and (4) cured and identify key determinants of CoC stage drop-off (Aim 1). These CoC data will allow for parameterization of new epidemic models that evaluate the impact of various scenarios of efforts to improve CoC proportions within each subgroup, identifying combinations of strategies that could achieve elimination (Aim 2). In collaboration with our partners in End Hep C SF, we will conduct a series of iterative consensus meetings with diverse experts to adapt modeling projections to create evidence-based elimination roadmaps that include annual intervention targets and benchmarks that are context-specific and feasible given programmatic realities in San Francisco (Aim 3). These elimination roadmaps will respond to identified needs and barriers to address gaps along each CoC, while also ensuring realistic benchmarks to achieve elimination targets. Doing so will be replicable in other cities, enhancing current NIH research dollars invested in these subgroups and laying the groundwork for subsequent R01 applications to test specific evidence-based HCV interventions.!